We investigated the nature of resistance to Friend murine leukemia virus (F-MuLV) in transgenic mice carrying the Fv4 env transgene and worked on a related system for HIV. Transgenic mice expressing high levels of the Fv4 env transgene were completely resistant to infection with F-MuLV while mice expressing low levels of the transgene had enhanced ability to recover from infection. Resistance was transferrable from transgenic mice via bone marrow transplantation. Bone marrow chimeras containing a mixture of transgenic and non- transgenic bone marrow-derived cells were slightly resistant in that they had enhanced ability to recover from infection. Whereas bone marrow transplantation was very effective prophylactically in preventing infection, it was not very effective in treating an already established infection. We are attempting to determine whether the Fv4 gene alters the immune response to the antigenically-related F-MuLV, and are investigating alternative ways of introducing the Fv4 gene into mice as gene therapy. To build an HIV system comparable to Fv4, we made a neo-containing retroviral vector that confers stable expression of HIV vpu, env and rev after infection and selection with G418. Mutant (syncytia-negative) env genes were substituted into this vector to generate HeLa-CD4 cell clones that stably express envelope. This vector was found to down-regulate CD4 about 10-fold but only in a portion (about 40%) of cells derived from single clones. The reason for the inhomogeneity of down-regulation of CD4 is not understood but it is apparently not related to phase of the cell cycle. Clones expressing env were more, rather than less, susceptible to HIV, probably due to co-expression of rev, since clones expressing rev alone were also more susceptible to HIV. We are investigating the effects of this HIV vector system in CD4-positive lymphocytes and attempting to further down-regulate CD4 in order to block infection with HIV.